P1 Affective disorders and antidepressants S 137 S. (1992) A double-blind comparative, multicenter study comparing paroxe- tine with fluoxetine in depressed patients. Acta. Psychiatrica Scandinavia 87, 141-145. [3] Neylan, T.C. (1995) Treatment of Sleep Disturbances in DepressedPatients. J. Clin. Psych. 56 (suppl. 2), 56~51. ~ T h e role of paroxetine in the treatment of anxiety disorders D.S. Baldwin, J. Birtwistle. University Department of Psychiatry, Royal South Hants Hospital, Southampton, UK Considerable evidence supporting the role of altered brain 5-hydrox- ytryptamine (5-HT) function in the anxiety disorders has provided a rationale for investigating 5-HT selective agents for their treatment. In this presentation, the use of the selective serotonin reuptake inhibitor (SSRI) paroxetine in the treatment of panic disorder, obsessive com- pulsive disorder (OCD) and social phobia, will be reviewed. These are common anxiety disorders, with lifetime prevalence rates estimated up to 13% (Kessler et al., 1994). They typically affect adolescents and young adults, resulting in considerable educational, occupational, and social disability. As these anxiety disorders are chronic and relapsing, it is important that treatment is effective ih both the short term and the long term, and is well tolerated. Paroxetine was the first SSRI to be licensed for use in panic disorder. In a clinical trial programme involving almost 1000 patients with panic disorder, paroxetine was shown to be at least as effective as clomipramine in reducing the frequency of panic attacks, with evidence that it has an earlier onset of action and a superior tolerability profile. During long-term treatment, paroxetine was effective in sustaining an improvement in panic symptoms and preventing relapse (Lecrubier et al., 1997). In addition, the incidence of adverse events during long-term treatment with paroxetine was not significantly different from placebo. Anxiolytics and antidepressants that are non-serotonin-selective are generally ineffective in the treatment of OCD, while clomipramine, and several SSRIs are efficacious. An extensive clinical trial programme has investigated paroxetine in the treatment of OCD in around 1000 patients. The results demonstrated that paroxetine was an effective, well-toler- ated treatment for OCD, at least as effective and better tolerated than clomipramine (Zohar and Judge, 1996). Efficacy was maintained during long-term treatment with paroxetine, and relapse was prevented. There are no precise clinical guidelines for the management of social phobia, but there is growing support for the use of some members of the SSR1 class of antidepressant. A 12-week, placebo-controlled study has demonstrated the efficacy of paroxetine in social phobia: paroxetine pro- duced a significant, continuous clinical benefit from week four onwards, compared with placebo. Overall, the data suggested that paroxetine is an effective agent for the treatment of generalised social phobia and that aspects of quality of life may be positively improved. In conclusion, clinical studies carried out to date show that paroxetine is an effective and well-tolerated treatment, not only for depression, but also for specific anxiety disorders. References [1] Kessler,R.C., McGonagle, K.A., Zhao, S., et al. (1994) Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results ti'om the National Comorbidity Survey. Arch. Gen. Psychiatry 51, 8-19. [2] Lecrubier, Y., Judge, R. and the Collaborative Paroxetine Panic Study Investi- gators. (1997) Long-term evaluation of paroxetine, clomipramine and placebo in panic disorder. Acta Psychiatr. Scand. 95, 153-160. [3] Zohar,J. and Judge, R. (1996) Paroxetine versus clomipraminein the treatment of obsessivecompulsivedisorder. Br. J. Psychiatry 169, 468-474. ~ Paroxetine levels and clinical plasmatic response m major depression F.J. Baron, V. Perez, I. Ferrer, D. Puigdemont, J. Queralto, M. Figueras, E. Alvarez. Psychiatric Department of Hospital de la Santa Creu i Sant Pau, Barcelona, Espana Paroxetine is a selective serotonin reuptake inhibitor with significant antidepressant properties. Determinate plasmatic levels let us to now a possible relationship between plasma levels of antidepressant drugs and therapeutic response, reassurance treatment compliance as well as to know the drug pharmacokinetic in patients with many side effects. The objective of the study was to determine the possible relation between the clinical response to antidepressive treatment with paroxetine and the drug's plasma levels. Methods: 87 patients, 27 men and 60 women, mean age was 48.4 years with Major depressive illness according to the DSM-III-R criteria. 60% of patients received doses of 20 mg of paroxetine and 40% received doses of 40 rag. Clinical response was assessed using the Hamilton Scale for Depression (HAM-D) in the sixth week. The plasma levels of Paroxetine were measured in the fourth week (at steady-state) by means H.P.L.C. Results: 60% of patients had a score <9 on the HAIvI-D in the sixth week of treatment. The average plasma level of paroxetine was 62.30 ng/ml. There was not significant linear correlation betveeen plasmatic concentrations of paroxetine and the decrease in the Hantilton score. By means of serial Chi-score calculation we explored a possible minimum plasmatic concentration which less therapeutic response. Conclusions: We discuss the pharmacokinetic an clinical implications of the results. [ ~ MAO-A and MAO-B differ in their stereoselective biotransformation of citalopram in human liver B. Rochat, M. Kosel, P. Baumann, G. Boss 1, B. Testa 1 M. Gillet 2. Dgpartement universitaire de psychiatric adulte, CH-I O08 Prilly-Lausanne; 11CT, Ecole de Pharmacie, Universitd de Lausanne, Lausanne-Dorigny; 2Service de Chirurgie, CHUV, 1005 l~usanne, Switzerland "['he N-demethylation of the chiral SSRI citalopram (CIT) by cytochrome P-450 has recently been described (Rochat et al., 1997). No data are avail- able on the enzymes involved in the deamination of CIT, desmethyl-CIT (DCIT) and didesmethyl-CIT (DDCIT) to the propionic acid derivative (CIT-PROP). The aim of the present study was to describe the role of MAO-A and MAO-B in the stereoselective deamination of these drugs, and that of aldehyde oxidases (At) in the subsequent formation of CIT-PROP in human liver preparations. Therefore, incubation mixtures (INCMIX) were prepared with com- hined microsomal and cytosolic fractions of livers from 4 different donors. Racemic CIT, DCIT and DDCIT (500/zM each, separately) were added to the incubation mixtures and the formation of the enantiomers S- and R-CIT-PROP was observed in the presence and absence of NADPH regenerating system (NADP) and/or enzyme inhibitors. The metabolites were analysed by a stereoselective method (Rochat et al., 1995). Incubation of rac-CIT, rac-DCIT and rac-DDCIT in presence (or ab- ~;ence) of NADP in INCMIX showed that CIT-PROP formation was ~;ubstrate dependent, in decreasing order from: S-DCIT: 109.8 ng (154.6 ng)> S-DDCIT: 86.4 ng (119.9 ng) > S-CIT: 33.2 ng (29.5 ng) > R-DCIT: 27.9 ng (47.4 ng) > R-CIT: 14.4 ng (26.7 ng) > R-DDCIT: 8.6 ng (13.0 ng). These results indicate that, in this incubation sys- tem, the enzymes involved in CIT-PROP formation are not essentially NADP-dependent and therefore differ from cytochrome P-450. Suspicion that MAt is implicated in the biotransfon'nation of these amines to CIT-PROP was confirmed by the finding that the non-selec- tive MAt inhibitor phenelzine (50 /zM) almost abolished CIT-PROP production. Using selective MAt inhibitors (0.5 #M) of MAO-A and MAt-B, clorgyline and selegiline, respectively, inhibition of the deami- nation of CIT (tertiary amine) was more pronounced with clorgyline, but that of DDCIT (primary amine) was stronger with selegiline. Moreover, the S-enantiomers of the three amines appeared to be preferentially metabolised by MAt-A, while MAO-B is preferentially involved in deamination of the R-enantiomers. With regard to the second metabolic step, experiments have been carried out with menadione, an At inhibitor. The results add evidence to a role of MAt and At in the metabolism of CIT, DCIT and DDCIT to CIT-PROP via an aldehyde intermediate. The clinical implications of a combination of CIT with MAOI should be discussed.